WO2018119291A1 - Synthetic methods - Google Patents

Abstract

Provided is a method of crystallizing (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride.

Description

SYNTHETIC METHODS

[0001] This application claims priority to U.S. Provisional Application No. 62/437,657 filed December 21, 2016, and U.S. Provisional Application No. 62/438,437 filed

December 22, 2016, each of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to methods for crystallizing Crystalline Form A of

(lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

BACKGROUND OF THE INVENTION

[0003] (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-l- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a compound useful as an unbalanced triple reuptake inhibitor (TRI), most potent towards norepinephrine reuptake (NE), one-sixth as potent towards dopamine reuptake (DA), and one-fourteenth as much towards serotonin reuptake (5- HT). This compound and its utility are disclosed in more detail in U.S. Patent Publication No. 2007/0082940, which is hereby incorporated by reference in its entirety.

[0004] Active pharmaceutical ingredients can exist in different physical forms (e.g., liquid or solid in different crystalline, amorphous, hydrate, or solvate forms), which can vary the processability, stability, solubility, bioavailability, pharmacokinetics (absorption, distribution, metabolism, excretion, or the like), and/or bioequivalency of the active pharmaceutical ingredient and pharmaceutical compositions comprising it. Whether a compound will exist in a particular polymorph form is unpredictable. It is important in pharmaceutical development to generate and identify advantageous physical forms (e.g., free base or salt in solid, liquid, crystalline, hydrate, solvate, or amorphous forms) of active pharmaceutical ingredients.

Therefore, there remains a need for particular polymorph forms of (lR,5S)-l-(naphthalen-2-yl)- 3-azabicyclo[3.1.0]hexane.

SUMMARY OF THE INVENTION

[0005] (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-l-

(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane ("the Compound") is shown as Formula I below:

Formula I

[0006] (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride exhibits different non-solvate and non-hydrate crystalline forms - Crystalline Form A, Crystalline Form B, and Crystalline Form C, which are described in International Application No.

PCT/US2016/038256, which is hereby incorporated by reference in its entirety.

[0007] Phase transitions of solids can be thermodynamically reversible or irreversible.

Crystalline forms that transform reversibly at a specific transition temperature (T_t) are enantiotropic polymorphs. If the crystalline forms are not interconvertible under these conditions, the system is monotropic (one thermodynamically stable form).

[0008] Crystalline Forms A, B, and C are anhydrous enantiotropes of (1R,5S)-1-

(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. Crystalline Form C is the stable solid phase below the transition temperature T_t,c→_B, Crystalline Form B is the stable solid phase between T_t,c→e and T_T,B→A, and Crystalline Form A is the stable solid phase above T_T,B→A- T_t,c→B is expected below 2 °C. T_t,c→A will be between 2 °C and ambient temperature, and T_IB→A is between 37 and 54 °C.

[0009] Owing to kinetic constraints, the thermodynamic transformation of Crystalline

Form A to Crystalline Form B is hindered. Therefore, surprisingly, Crystalline Form A appears to be sufficiently kinetically stable so as to persist in the solid state under temperature conditions where it is thermodynamically metastable.

[0010] In Example 5, Crystalline Form B is obtained from a slurry of (1R,5S)-1-

(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in water.

[0011] In Example 6, Crystalline Form B is obtained from stirring (1R,5S)-1-

(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in Special Industrial 200 (ethanol denatured) over weekend at ambient temperature.

[0012] In Example 12, dissolving (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in hot ethyl alcohol 200 (Special Industrial denatured) and concentrating and stirring at 18 °C yields (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Crystalline Form A with evidence of low intensity peaks attributable to Crystalline Form B.

[0013] In Example 13, mixing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride with EtOH Special Industrial, heating, concentrating, and cooling to room temperature yields Crystalline Form A and Crystalline Form B.

[0014] The inventors have found that (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms may be reproducibly prepared by crystallizing from pure ethanol (e.g., absolute ethanol).

In contrast, denatured ethanol comprises components that favour formation of Crystalline Form

B.

[0015] The inventors have also found that (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms may be reproducibly prepared by using (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material having an enantiomeric excess (%EE) of (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

[0016] Provided is a method (Method la) of crystallizing (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms (e.g., exhibits an XRPD pattern as shown in any one of Figures 1, 8, 10, or 17) comprising mixing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material and pure ethanol, e.g., ethanol having a purity of 85% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 99% or greater, e.g., 99.5% or greater.

[0017] Further provided is a method (Method lb) of crystallizing (lR,5S)-l-(naphthalen-

2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms (e.g., exhibits an XRPD pattern as shown in any one of Figures 1, 8, 10, or 17) comprising crystallizing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material having an enantiomeric excess (%EE) of (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride of 51% or greater, e.g., 60% or greater, e.g., 70% or greater, e.g., 80% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 96% or greater, e.g., 97%) or greater, e.g., 98% or greater, e.g. 99% or greater.

[0018] Further provided are Method la and lb as follows: Method lb comprising mixing the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material and pure ethanol, e.g., ethanol having a purity of 85% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 99% or greater, e.g., 99.5% or greater.

Any one of Method la, lb, et seq., wherein the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material has an enantiomeric excess (%EE) of (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride of 51% or greater, e.g., 60% or greater, e.g., 70% or greater, e.g., 80%) or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 96% or greater, e.g., 97% or greater, e.g., 98% or greater, e.g. 99% or greater.

Any one of Method la, lb, et seq. comprising dissolving the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol.

Any one of Method la, lb, et seq. comprising dissolving the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in 1- 20 ml of the ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 5-20 ml of the ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 10-20 ml of the ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 14 ml of the ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material.

Any one of Method la, lb, et seq. wherein the concentration of the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol is 10-150 mg/ml, e.g., 20-150 mg/ml, e.g., 50-100 mg/ml, e.g., 50 mg/ml, e.g., 75 mg/ml.

Any one of Method la, lb, et seq. comprising dissolving the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol under heat, e.g., heating a mixture of the (lR,5S)-l-(naphthalen-2-yl)- 3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol to 30 °C or higher (e.g., 30 °C-100 °C), e.g., 40 °C or higher (e.g., 40 °C-100 °C), e.g., 50 °C or higher (e.g., 50 °C-100 °C), e.g., 60 °C or higher (e.g., 60 °C-100 °C), e.g., 70 °C or higher (e.g., 70 °C-100 °C, e.g., 70 °C), e.g., 80 °C or higher (e.g., 80 °C-100 °C), e.g., 90 °C or higher (e.g., 90 °C-100 °C), e.g., 100 °C or higher. Any one of Method la, lb, et seq. comprising improving the color of the mixture by removing colored impurities, for example, by filtering through an encapsulated carbon filter and/or adding charcoal (e.g., loose charcoal slurry in ethanol) and filtering to remove the charcoal.

Any one of Method la, lb, et seq. further comprising concentrating the ethanol. Any one of Method la, lb, et seq. further comprising concentrating the ethanol under vacuum.

Any one of Method la, lb, et seq. further comprising concentrating the ethanol under heat, e.g., at 80 °C or less (e.g. above room temperature to 80 °C), e.g., 70 °C or less (e.g., above room temperature to 70 °C), e.g., 60 °C or less (e.g., above room temperature to 60 °C), e.g., 50 °C or less (e.g., above room temperature to 50 °C, e.g., 50 °C), e.g., 40 °C or less (e.g., above room temperature to 40 °C), e.g., 30 °C or less (e.g., above room temperature to 30 °C).

Any one of Method la, lb, et seq. further comprising concentrating the ethanol to 1-10 ml ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 8 ml ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material.

Any one of Method la, lb, et seq. further comprising cooling the ethanol, e.g., to 30 °C or less (e.g., 0 °C-30 °C), e.g., room temperature or less (e.g., 0°C to room temperature), e.g., 20 °C or less (e.g., 0 °C-20 °C), e.g., 10 °C or less (e.g., 0°C- 10 °C), e.g., 5 °C or less (e.g., 0 °C-5 °C), e.g., 18 °C, e.g., 5 °C.

Method 1.12 further comprising stirring the ethanol during and/or after cooling. Any one of Method la, lb, et seq. further comprising seeding with (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A, e.g., seeding the mixture of the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material and the ethanol with (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A.

Any one of Method la, lb, et seq. further comprising isolating (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms, e.g., isolating by filtration, e.g., isolating by filtration and, optionally, rinsing with a solvent, e.g., ethanol (e.g., the pure ethanol) and/or isopropyl acetate.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern as shown in any one of Figures 1, 8, 10, or 17.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern comprising the observed 2-theta (°) values as set forth in Table 6a in Example 3 (observed 2-theta (°) values are also shown in Figure 11), wherein the XRPD is measured using an incident beam of Cu radiation of wavelength 1.54059 A.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern comprising the representative 2-theta (°) values as set forth in Table 6b in Example 3, wherein the XRPD is measured using an incident beam of Cu radiation of wavelength 1.54059 A.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern comprising the characteristic 2-theta (°) values as set forth in Table 6c in Example 3, wherein the XRPD is measured using an incident beam of Cu radiation of wavelength 1.54059 A.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern comprising the d-spacing (A) values as set forth in Table 6a in Example 3.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern comprising the d-spacing (A) values as set forth in Table 6b in Example 3.

Any one of Method la, lb, et seq. wherein the Crystalline Form A exhibits an XRPD pattern comprising the d-spacing (A) values as set forth in Table 6c in Example 3. [0019] Further provided is Crystalline Form A made by any one of Method la, lb, et seq.

[0020] Further provided is a pharmaceutical composition comprising Crystalline Form

A substantially free of other crystalline forms, e.g., Crystalline Form A substantially free of other crystalline forms made by any one of Method la, lb, et seq.

[0021] Further provided is a method for making a pharmaceutical composition comprising any of Crystalline Form A substantially free of other crystalline forms, wherein the method comprises:

making Crystalline Form A substantially free of other crystalline forms as in any one of Method la, lb, et seq.,

isolating the Crystalline Form A substantially free of other crystalline forms, and admixing the isolated Crystalline Form A with a pharmaceutically acceptable diluent or carrier.

[0022] Crystalline Form A substantially free of other crystalline forms is useful as an unbalanced triple reuptake inhibitor (TRI), most potent towards norepinephrine reuptake (NE), one-sixth as potent towards dopamine reuptake (DA) and one-fourteenth as much towards serotonin reuptake (5-HT). Therefore, the Crystalline Form A substantially free of other crystalline forms, as described herein, is useful for the prophylaxis or treatment of a disorder and/or alleviation of associated symptoms of any disorder treatable by inhibiting reuptake of multiple biogenic amines causally linked to the targeted CNS disorder, wherein the biogenic amines targeted for reuptake inhibition are selected from norepinephrine, and/or serotonin, and/or dopamine. Accordingly, further provided is a method for the prophylaxis or treatment of any of the following disorders:

• attention deficit hyperactivity disorder (ADFID) and related behavioral disorders, as well as forms and symptoms of substance abuse (alcohol abuse, drug abuse), obsessive compulsive behaviors, learning disorders, reading problems, gambling addiction, manic symptoms, phobias, panic attacks, oppositional defiant behavior, conduct disorder, academic problems in school, smoking, abnormal sexual behaviors, schizoid behaviors, somatization, depression, sleep disorders, generalized anxiety, stuttering, and tic disorders. Further disorders are disclosed in U.S. Publication No. 2007/0082940, which is hereby incorporated by reference in its entirety; • depression, anxiety disorders, autism, traumatic brain injury, cognitive impairment, and schizophrenia (particularly for cognition), obesity, chronic pain disorders, personality disorder, and mild cognitive impairment;

• panic disorder, posttraumatic stress disorder, obsessive compulsive disorder,

schizophrenia and allied disorders, obesity, tic disorders, Parkinson's disease;

• disorders disclosed in International Publication No. WO 2013/019271, which is hereby incorporated by reference in its entirety;

• fragile X-associated disorder;

• fragile X-associated disorder wherein the patient was refractory to a prior course of

treatment for the fragile X-associated disorder;

• attention-deficit/hyperactivity disorder (ADHD) wherein the ADHD is co-morbid with one or both of anxiety and depression (e.g., depression), e.g., in a patient with a fragile X- associated disorder;

• autism spectrum disorder (ASD);

• disorders disclosed in International Publication No. WO 2015/089111, which is hereby incorporated by reference in its entirety,

comprising administering to a patient in need thereof a therapeutically effective amount of Crystalline Form A substantially free of other crystalline forms, e.g., Crystalline Form A as made by any one of Method la, lb, et seq.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 depicts a high-resolution X-ray powder diffraction (XRPD) pattern of

Crystalline Form A.

[0024] Figure 2 depicts an overlay of X-ray powder diffraction (XRPD) patterns of

Crystalline Form A, Form B, and Form C (from top to bottom): Figure 2 A depicts a high resolution X-ray powder diffraction pattern of Crystalline Form A; Figure 2B depicts an X-ray powder diffraction pattern of Crystalline Form B; and Figure 2C depicts an X-ray powder diffraction pattern of Crystalline Form C.

[0025] Figure 3 depicts an X-ray powder diffraction (XRPD) pattern of Crystalline Form

B. [0026] Figure 4 depicts a high-resolution X-ray powder diffraction (XRPD) pattern of

Crystalline Form B.

[0027] Figure 5 depicts an X-ray powder diffraction (XRPD) pattern of Crystalline Form

C.

[0028] Figure 6 depicts a high-resolution X-ray powder diffraction (XRPD) pattern of

Crystalline Form C.

[0029] Figure 7 depicts an overlay of X-ray powder diffraction (XRPD) patterns of

Crystalline Form A, Form B, and Form C (from top to bottom): Figure 7 A depicts an X-ray powder diffraction pattern of Crystalline Form B (slow cooling in IP A, solids precipitate in refrigerator); Figure 7B depicts an X-ray powder diffraction pattern of Crystalline Form C + Crystalline Form B (slow crystalline cooling in IP A, with seeds, solids precipitate in freezer); Figure 7C depicts an X-ray powder diffraction pattern of Crystalline Form C +

Crystalline Form A (slow cooling in IP A, solids precipitate in freezer); Figure 7D depicts an X- ray powder diffraction pattern of Crystalline Form B (slow cooling in IP A, solids precipitate in freezer); Figure 7E depicts an X-ray powder diffraction pattern of Crystalline Form B +

Crystalline Form A (crash cooling in IP A, solids precipitate in dry ice/IP A); Figure 7F depicts an X-ray powder diffraction pattern of Crystalline Form A + Crystalline Form C (slow cooling in IP A, solids precipitate in freezer); and Figure 7G depicts an X-ray powder diffraction pattern Crystalline Form C (slow cooling in IP A).

[0030] Figure 8 depicts an XRPD pattern of Crystalline Form A.

[0031] Figure 9 depicts an XRPD pattern comparison of (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride from Examples 1 and 3 (top: Example 3; bottom:

Example 1) (patterns are offset along the y-axis for comparison).

[0032] Figure 10 depicts an XRPD pattern of Crystalline Form A collected with Cu Ka radiation.

[0033] Figure 11 shows observed peaks for the XRPD pattern depicted in Figure 10 collected with Cu Ka radiation.

[0034] Figure 12 depicts an XRPD pattern of Crystalline Form B.

[0035] Figure 13 shows observed peaks for the XRPD pattern depicted in Figure 12 collected with Cu Ka radiation.

[0036] Figure 14 depicts an XRPD pattern of Crystalline Form C. [0037] Figure 15 shows observed peaks for the XRPD pattern depicted in Figure 14 collected with Cu Ka radiation.

[0038] Figure 16 depicts proposed energy - temperature plots for Crystalline Forms A,

B, and C.

[0039] Figure 17 depicts an XRPD pattern of Crystalline Form A.

[0040] Figure 18 depicts an XRPD pattern of Crystalline Form B.

[0041] Figure 19 depicts an XRPD pattern of a mixture of Crystalline Form A and a minor quantity of Crystalline Form B.

[0042] Figure 20 depicts an XRPD pattern of a mixture of Crystalline Forms A and B.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "the Compound" refers to (lR,5S)-l-(naphthalen-2-yl)-

3-azabicyclo[3.1.0]hexane, also known as (+)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. The term "the Compound in hydrochloric acid addition salt form" refers to (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride or (+)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride having the following structure:

[0044] The term "substantially free of other crystalline forms" refers to less than 10 weight %, in some embodiments less than 5 weight %, in some embodiments less than 2 weight %, still in some embodiments less than 1 weight %, still in some embodiments less than 0.1 weight %, yet in some embodiments less than 0.01 weight % of other crystalline forms.

[0045] The term "solvate" refers to crystalline solid adducts containing either

stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. Therefore, the term "non-solvate" form herein refers to crystalline forms that are free or substantially free of solvent molecules within the crystal structures. Similarly, the term "non- hydrate" form herein refers to salt crystals that are free or substantially free of water molecules within the crystal structures. [0046] The term "amorphous" form refers to solids of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.

[0047] The term "patient" includes human and non-human. In one embodiment, the patient is a human. In another embodiment, the patient is a non-human.

[0048] The term "anti-solvent" means a solvent in which the Compound and/or the

Compound in hydrochloric acid addition salt form ((lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride) has low solubility or is insoluble. For instance, an anti- solvent includes a solvent in which the Compound and/or the Compound in hydrochloric acid addition salt form has a solubility of less than 35 mg/ml, e.g., a solubility of 10-30 mg/ml, e.g., a solubility of 1-10 mg/ml, e.g., a solubility of less than 1 mg/ml.

[0049] The term "XRPD" means X-ray powder diffraction.

[0050] It is to be understood that an X-ray powder diffraction pattern of a given sample may vary (standard deviation) depending on the instrument used, the time and temperature of the sample when measured, and standard experimental errors. Therefore, the 2-theta values, d- spacing values, heights and relative intensity of the peaks will have an acceptable level of deviation. For example, the values may have an acceptable deviation of, e.g., about 20%, 15%, 10%), 5%), 3%), 2% or 1%>. In a particular embodiment, the 2-theta values (°) or the d-spacing values (A) of the XRPD pattern of the crystalline forms disclosed herein may have an acceptable deviation of ± 0.2 degrees and/or ± 0.2 A. Further, the XRPD pattern of the crystalline forms disclosed herein may be identified by the characteristic peaks as recognized by one skilled in the art. For example, the crystalline forms disclosed herein may be identified by, e.g., two characteristic peaks, in some instances, three characteristic peaks, in another instance, five characteristic peaks. Therefore, the term "substantially as" set forth in a particular table or depicted or shown in a particular figure refers to any crystal which has an XRPD having the major or characteristic peaks as set forth in the tables/figures as recognized by one skilled in the art.

[0051] Under most circumstances for XRPDs, peaks within the range of up to about 30°

2Θ are selected. Rounding algorithms are used to round each peak to the nearest 0.1° or 0.01° 2Θ, depending upon the instrument used to collect the data and/or the inherent peak resolution. Peak position variabilities are given to within ±0.2° 2Θ. [0052] Preferred orientation is the tendency for crystals to align themselves with some degree of order. This preferred orientation of the sample can significantly affect peak intensities, but not peak positions, in an experimental powder diffraction pattern.

[0053] The wavelength used to calculate d-spacing (A) values herein is 1.5405929A, the Cu-K_ai wavelength (Phys. Rev., A56 (6), 4554-4568 (1997)).

[0054] Per USP guidelines, variable hydrates and solvates may display peak variances greater than ±0.2° 2Θ.

[0055] "Prominent peaks" are a subset of the entire observed peak list and are selected from observed peaks by identifying preferably non-overlapping, low-angle peaks, with strong intensity.

[0056] If multiple diffraction patterns are available, then assessments of particle

statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as "representative peaks." In general, the more data collected to determine representative peaks, the more confident one can be of the classification of those peaks.

[0057] "Characteristic peaks," to the extent they exist, are a subset of representative peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition).

Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ±0.2° 2Θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0058] As used herein, "therapeutically effective amount" refers to an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms. The specific dose of substance administered to obtain a therapeutic benefit will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific substance administered, the route of administration, the condition being treated, and the individual being treated.

[0059] A dose or method of administration of the dose of the present disclosure is not particularly limited. Dosages employed in practicing the present disclosure will of course vary depending, e.g. on the mode of administration and the therapy desired. In general, satisfactory results, are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. An indicated daily dosage for oral administration may be in the range of from about 0.75 mg to 200 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 mg to 75 mg or 150 mg, e.g. from about 0.2 mg or 2.0 mg or 50 mg or 75 mg or 100 mg to 200 mg or 500 mg of Crystalline Form A substantially free of other crystalline forms as disclosed herein, e.g., Crystalline Form A made by any of Method la, lb, et seq., together with a pharmaceutically acceptable diluent or carrier therefor.

[0060] Crystalline Form A substantially free of other crystalline forms as disclosed herein may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, including by sustained release, although various other known delivery routes, devices and methods can likewise be employed. In some embodiments, provided is a sustained release pharmaceutical composition, e.g., an oral sustained release pharmaceutical composition, comprising Crystalline Form A substantially free of other crystalline forms as disclosed herein, e.g., Crystalline Form A as made by any one of Method la, lb, et seq.

[0061] Further dosages and formulations are provided in International Publication

No. WO 2015/089111 and International Publication No. WO 2015/102826, each of which are hereby incorporated by reference in their entirety.

[0062] (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in hydrochloric acid addition salt form may be prepared as described in U.S. Patent Publication No. 2007/0082940 or International Publication No. WO 2013/019271, both of which are incorporated herein by reference in their entirety.

[0063] While both U. S. Patent Publication No. 2007/0082940 and International

Publication No. WO 2013/019271 describe synthesis of (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride, neither discuss any particular crystal form of (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

[0064] Crash Cool (CC): Solutions are prepared in various solvents at an elevated temperature and filtered warm through a 0.2-μπι nylon filter into a pre-cooled vial. The vial is placed in a (dry ice + isopropanol) cooling bath. Samples are placed into a freezer if no solids are observed to immediately precipitate. The resulting solids are isolated by vacuum filtration and analyzed.

[0065] Relative Humidity Stress: Solids are stored at approximately 40 °C/75% RH condition for a measured time period by placing the solids into a vial inside a sealed

temperature/humidity chamber at the controlled condition. Samples are analyzed after removal from the stress environment.

[0066] Slow Cooling (SC): Solutions are prepared in various solvents at an elevated temperature. The solutions are filtered warm through a 0.2-μπι nylon filter into a warm vial. The vial is capped and left on the hot plate, and the hot plate is turned off to allow the sample to cool slowly to ambient temperature. If no solids are present after cooling to ambient temperature, the sample is placed in a refrigerator and/or freezer for further cooling. Solids are collected by vacuum filtration and analyzed.

[0067] Slurry Experiments: Suspensions are prepared by adding enough solids to a given solvent so that excess solids are present. The mixture is then agitated in a sealed vial at ambient temperature or an elevated temperature. After a given period of time, the solids are isolated by vacuum filtration and analyzed.

[0068] XRPD Overlays: The overlays of XRPD patterns are generated using Pattern

Match 2.3.6.

[0069] Instrumental Techniques: The test materials in this study are analyzed using the instrumental techniques described below.

[0070] X-ray Powder Diffraction (XRPD): Inel XRG-300. X-ray powder diffraction analyses are performed on an Inel XRG-3000 diffractometer, equipped with a curved position- sensitive detector with a 2Θ range of 120°. Real time data is collected using Cu Ka radiation at a resolution of 0.03 °2Θ. The tube voltage and amperage are set to 40 kV and 30 mA, respectively. Patterns are displayed from 2.5 to 40 °2Θ to facilitate direct pattern comparisons. Samples are prepared for analysis by packing them into thin-walled glass capillaries. Each capillary is mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. Instrument calibration is performed daily using a silicon reference standard. The data acquisition and processing parameters are displayed on each pattern found in the data section.

[0071] X-ray Powder Diffraction (XRPD): Bruker D-8 Discover Diffractometer. XRPD patterns are collected with a Bruker D-8 Discover diffractometer and Bruker' s General Area Diffraction Detection System (GADDS, v. 4.1.20). An incident beam of Cu Ka radiation is produced using a fine-focus tube (40 kV, 40 mA), a Gobel mirror, and a 0.5 mm double-pinhole collimator. The sample is packed between 3-micron thick films to form a portable disc-shaped specimen. The prepared specimen is loaded in a holder secured to a translation stage and analyzed in transmission geometry. The incident beam is scanned and rastered to optimize orientation statistics. A beam-stop is used to minimize air scatter from the incident beam at low angles. Diffraction patterns are collected using a Hi-Star area detector located 15 cm from the sample and processed using GADDS. Prior to the analysis a silicon standard is analyzed to verify the Si 111 peak position. The data acquisition and processing parameters are displayed on each pattern found in the data section.

[0072] X-ray Powder Diffraction (XRPD): PANalytical X'Pert Pro Diffractometer.

XRPD patterns are collected using a PANalytical X'Pert Pro diffractometer. The specimen is analyzed using Cu radiation produced using an Optix long fine-focus source. An elliptically graded multilayer mirror is used to focus the Cu Ka X-rays of the source through the specimen and onto the detector. The specimen is sandwiched between 3-micron thick films, analyzed in transmission geometry, and rotated parallel to the diffraction vector to optimize orientation statistics. A beam-stop, short antiscatter extension, antiscatter knife edge, and helium purge are used to minimize the background generated by air scattering. Soller slits are used for the incident and diffracted beams to minimize axial divergence. Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen. The data-acquisition parameters of each diffraction pattern are displayed above the image of each pattern in the data section. Prior to the analysis, a silicon specimen (NIST standard reference material 640d) is analyzed to verify the position of the silicon 111 peak.

[0073] Abbreviations

acetonitrile (ACN) birefringence (B)

brine (saturated aqueous solution of sodium chloride) density (d)

dichloromethane (DCM)

equivalents (eq)

ethanol (EtOH)

ethyl acetate (EtOAc)

extinction (E)

formula weight (FW)

gram (g)

hour or hours (h, hrs)

hexafluoroisopropanol (HFIPA)

high performance (pressure) liquid chromatography (HPLC) isopropanol (IP A)

isopropyl acetate (IP Ac)

isopropyl ether (IPE)

kilogram (kg)

liters (L)

methanol (MeOH)

methyl ethyl ketone (MEK)

minute(s) (min)

millilitres (mL)

molarity of a solution (mol/L) (M)

molecular weight (MW)

moles (mol)

room temperature (RT)

saturated (sat)

sodium hexamethyldisilylazane (NaHMDS)

starting material (SM)

tetrahydrofuran (THF)

2,2,2,-trifluoroethanol (TFE) versus (vs)

weight (wt)

Example 1 - Preparation of Crystalline Form A

[0074] Charge 2-naphthylacetonitrile (1500 g, 8.97 mol, SM) to a 3-neck, 50 L round bottom flask equipped with an overhead stirrer, addition funnel, thermocouple, cooling bath, nitrogen inlet and drying tube. Charge tetrahydrofuran (6.0 L, 4 mL/g, SM) to the reaction vessel. Stir at room temperature until all of the 2-naphthylacetonitrile is dissolved. Charge (S)- (+)-epichlorohydrin (1081 g, 11.67 mol, 1.30 eq) to the reaction vessel. Cool the reaction mixture to an internal temperature of -28 °C. Use dry ice/acetone bath to cool. Dry ice added to bath intermittently to keep cooling bath between -35 and -25 °C during sodium bis(trimethylsilyl)amide addition. Charge a solution of sodium bis(trimethylsilyl)amide in THF (9.0 L, 18.0 mol, 2 mol eq) to the addition funnel and slowly add to the chilled reaction mixture at a rate such that the internal temperature remains at less than -14 °C. Addition requires 1 hr 40 minutes. During the addition the internal temperature is generally between -20 and -17 °C. After completion of the addition, the resulting solution is stirred at between -21 and -16 °C for 2 hours 30 minutes. Monitor the reaction by HPLC. Maintain -20 to -15 °C temperature of the reaction mixture while analyzing sample by HPLC.

[0075] HPLC assay at 2 hr 30 minutes shows reaction is not complete. Add additional sodium bis(trimethylsilyl)amide in THF (0.30 L, 0.60 mol, 0.067 mole eq) over 10 minutes via addition funnel, keeping the internal temperature of the reaction mixture less than -15 °C. Stir 15 minutes at which point HPLC assay shows reaction is complete. Charge borane- dimethylsulfide (2.25 L, 22.5 mol, 2.5 mole eq) complex via addition funnel at a rate such that the internal temperature of the reaction mixture remains below 0 °C. Addition requires 40 minutes. After completion of the borane addition slowly heat the reaction mixture to 40 °C. Once an internal temperature of 40 °C is obtained discontinue heating. A slow steady exotherm over approximately two hours is observed which results in a maximum internal temperature of 49 °C. Upon completion of the exotherm increase the internal temperature to 60 °C. Stir reaction mixture overnight at 60 °C. Monitor the reaction by HPLC. Maintain 60 °C temperature of the reaction mixture while analyzing sample by HPLC.

[0076] Charge additional borane-dimethylsulfide (0.35 L, 0.70 mol, 0.39 mole eq) to reaction mixture via addition funnel. Stir the reaction mixture 3 hours 30 minutes at 60 °C. Cool reaction mixture to room temperature.

[0077] To a second 3-neck, 50 L round bottom flask equipped with an overhead stirrer, thermocouple, cooling bath, and nitrogen inlet charge 2M HCl in water (17.3 L, 11.5 mL/g SM, prepared from 2.9 L concentrated HCl and 14.4 L water). Cool HCl/water solution to 3 °C. Slowly transfer room temperature reaction mixture containing the cyclopropyl amine to the chilled HCl solution at a rate such that the maximum internal temperature of the quench mixture is 23 °C. Quench requires 2 hr 50 minutes. When the reaction quench is complete, heat the two phase mixture to 50 °C. Stir for one hour at 50 °C. Cool to room temperature. Add

isopropyl acetate (6.0 L, 4 mL/g SM). Add water (7.5 L, 5 mL/g SM). Agitate mixture for a minimum of 15 minutes. Discontinue agitation and allow layers to settle for a minimum of 30 minutes. Discard the organic (upper) layer. Add aqueous ammonia (2.25 L, 1.5 mL/g SM) to the aqueous layer. Add isopropyl acetate (7.5 L, 5 mL/g). Agitate mixture for a minimum of 15 minutes. Discontinue agitation and allow layers to settle for a minimum of 30 minutes. Separate layers. Product is in the organic (upper) layer. Add isopropylacetate (7.5 L, 5 mL/g SM) to aqueous layer. Agitate mixture for a minimum of 15 minutes. Discontinue agitation and allow layers to settle for a minimum of 30 minutes. Separate layers. Product is in the organic (upper) layer. Combine the two isopropylacetate extracts. Add 5% dibasic sodium phosphate in water (6.0 L, 4 mL/g SM) to combined extracts. Agitate mixture for a minimum of 15 minutes.

Discontinue agitation and allow layers to settle for a minimum of 30 minutes. Separate layers and discard aqueous (lower) layer. Add saturated brine (6.0 L, 4 mL/g SM) to combined extracts. Agitate mixture for a minimum of 15 minutes. Discontinue agitation and allow layers to settle for a minimum of 30 minutes. Separate layers and discard aqueous (lower) layer.

Concentrate the final organic layer in a tared 20 L Buchi flask in vacuo. Obtain a total of 1967.6 g of a light orange waxy solid. Transfer solids to a 50 L 3-neck round bottom flask equipped with an overhead stirrer, thermocouple, heating mantel, nitrogen inlet and drying tube. Add isopropyl acetate (15 L, 10 mL/g SM). Heat the mixture to 50 °C. Add p-toluene sulfonic acid monohydrate (1586 g, 8.34 mol, 0.93 mole eq) in portions over 30 minutes keeping the temperature less than 60 °C. Upon completion of the addition discontinue heating and allow the mixture to cool to room temperature. Collect the solids by filtration. Wash the filtercake with isopropyl acetate (3 L, 2 mL/g SM). Wash the filtercake a second time with isopropyl acetate (3 L, 2 mL/g SM). Dry filtercake to a constant weight in the filter funnel by pulling air through the cake using vacuum. After an initial drying period the filtercake is broken up with a spatula and the cake agitated at intervals to promote drying. Obtain 2049 g of a white solid. HPLC assay: 98.2% for the main peak and a cis:trans ratio of 98.5: 1.5.

1 M NaOH 1.0 M NA 1 mL/g SM 2.1 L

3.75 mL/g

isopropyl acetate (back extraction) 102.13 0.872 7.6 L

SM

saturated brine NA NA 2 mL/g SM 4.1 L magnesium sulfate NA NA NA NA isopropylacetate (wash) 102.13 0.872 0.5 mL/g SM 1.0 L isopropylacetate (dilution) 102.13 0.872 3.5 mL/g SM 7.2 L hydrogen chloride in isopropyl

5.7 M NA 1.0 mol eq 0.90 L alcohol

1.13 mL/g

isopropylacetate (wash) 102.13 0.872 2.3 L

SM

1.13 mL/g

isopropylacetate (wash) 102.13 0.872 2.3 L

SM

7.45 mL/g

isopropyl alcohol 60.1 0.786 34.6 L

SM

isopropyl alcohol 60.1 0.786 1.5 mL/g SM 6.9 L isopropyl alcohol 60.1 0.786 1.5 mL/g SM 6.9 L

[0078] Note: Addition of 5 M NaOH to the reaction mixture is exothermic and requires active cooling.

[0079] Charge 2037.9 g (5.10 mol, 1.0 mol eq) of the naphthylcyclopropylamine-tosylate salt obtained above to a 50 L 3-neck round bottom flask equipped with an overhead stirrer, thermocouple, addition funnel, nitrogen inlet, drying tube and room temperature water bath. Charge 13.2 L of isopropyl acetate (IP Ac, 13.2 L, 6.5 mL/g SM) to the reaction flask and stir at room temperature to give a white slurry. Add 445 mL of thionyl chloride (6.13 mol, 1.2 mol eq) via the addition funnel keeping the temperature less than 25 °C. Addition requires 1 hr 5 minutes. Stir the thick slurry at ambient temperature for a minimum of two hours. Monitor the reaction by HPLC. Maintain the reaction mixture at ambient temperature while analyzing sample by HPLC. Add 5M NaOH (6.1 L, 30.5 mol, 6.0 mol eq) via addition funnel using an ice/water bath to keep less than 30 °C. Addition requires 1 hr 40 min. Monitor the reaction by HPLC. Maintain the reaction mixture at ambient temperature while analyzing sample by HPLC. Stir reaction mixture at 25 °C for 1 hr 5 min then allow layers to settle. Separate the layers. Wash the organic (upper) layer with 1M NaOH (2.1 L, 1 mL/g SM). Combine the two aqueous layers. Back extract the combined aqueous layers with isopropylacetate (7.6 L, 3.75 mL/g SM). Combine the washed organic layer and the back extract. Wash the combined organic layers with saturated brine (4.1 L, 2 mL/g SM). Dry organic layers over granular magnesium sulfate. Filter to remove solids. Wash filtercake with isopropyl acetate (1 L, 0.5 mL/g SM). Concentrate combined filtrate and wash in a 20 L Buchi Rotavap flask to a total volume of 4.2 L. Transfer to a 22 L 3 -neck round bottom flask equipped with overhead stirrer, addition funnel, thermocouple, cooling bath, nitrogen inlet, and drying tube. Dilute with isopropyl acetate (7.2 L, total volume of solution = 11.4 L, 5.6 mL/g SM). Add hydrogen chloride in isopropyl alcohol (5.7 M, 0.90 L, 5.13 mol, 1.0 mol eq) via addition funnel over 50 minutes at a rate such that the internal temperature remains below 30 °C. Stir the slurry for 45 minutes at room temperature. Filter to collect solids. Wash filtercake with isopropyl acetate (2.3 L, 1.13 mL/g SM). Wash filtercake a second time with isopropyl acetate (2.3 L, 1.13 mL/g SM). Partially dry filtercake by pulling air through the cake with vacuum. HPLC assay of the wet cake shows 96.3 area percent purity and an EE of 89.5%.

[0080] Combine wet cakes from this experiment and from another batch in a 50 L 3-neck round bottom flask equipped with overhead stirrer, heating mantel, thermocouple, reflux condenser, nitrogen inlet, and drying tube. Add isopropyl alcohol (34.6 L, 7.45 mL/g SM). Heat the slurry to reflux. Maintain reflux for three hours. Discontinue heating and allow to cool to room temperature. Filter to collect solids. Wash filtercake with isopropyl alcohol (6.9 L, 1.5 mL/g SM). Wash filtercake a second time with isopropyl alcohol (6.9L, 1.5 mL/g SM). Dry filtercake to a constant weight by pulling air through the cake using vacuum. Obtain 2009 g of product as a tan solid. HPLC: > 99.5%. Chiral HPLC: 95.4%.

[0081] Note: Minimal amount of ethanol necessary to completely dissolve the starting material should be used.

[0082] Charge (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1. OJhexane hydrochloride to a

50 L 3-neck round bottom flask equipped with an overhead stirrer, thermocouple, reflux condenser, heating mantel, nitrogen inlet and drying tube. Add ethanol (20 L, mL/g SM). Heat the stirred slurry to 77 °C. Add additional ethanol in 0.5 L aliquots and return mixture to reflux until all solids dissolve. Complete dissolution after the addition of 1.5 L additional ethanol, 21.5 L total. Discontinue heating and allow solution to cool to room temperature. Filter to collect solids. Wash filtercake with ethanol (4.3 L, 2.14 mL/g SM). Dry filtercake to a constant weight by pulling air through the filtercake using vacuum. Obtain 1435 g of light tan solids. Yield =

74%. HPLC: 99.5%. Chiral HPLC: 99.9%.

[0083] Charge the Compound in hydrochloric acid addition salt form ((1R,5S)-1-

(naphthalen-2-yl)-3-azabicyclo[3.1. OJhexane hydrochloride) (1406 g, 5.72 mol, 1.0 mol eq) (the compound obtained from the step above and another batch) to a 22 L, 3 -neck round bottom flask equipped with an overhead stirrer, heating mantel, thermocouple, and nitrogen inlet. Add water (14 L, 10 mL/g SM). Heat the slurry to an internal temperature of 34°C to dissolve all solids. Transfer to a large separately funnel. Add tetrahydrofuran (2.8 L, 2 mL/g SM). Add isopropyl acetate (2.8 L, 2 mL/g SM). Discontinue stirring and allow layers to separate. Discard the organic (upper) layer. Product is in the lower (aqueous) layer. To the aqueous (lower) layer add aqueous ammonia (1.14 L, 17.1 mol, 3.0 mol eq). Add isopropyl acetate (14.0 L, 10 mL/g SM). Agitate mixture for a minimum of 15 minutes. Discontinue agitation and allow layers to settle for a minimum of 30 minutes. Separate the layers. Product is in the organic (upper) layer. Add granular magnesium sulfate to the organic layer. Filter to remove solids. Wash the filtercake with isopropylacetate (1 L). Wash the filtercake a second time with isopropylacetate (1 L). Concentrate combined filtrate and washes in a 20 L Buchi rotavap flask to give an off-white solid. Charge solid to a 22 L round bottom flask equipped with overhead stirrer, thermocouple, addition funnel, nitrogen inlet and drying tube. Add isopropyl alcohol (14 L, 10 mL/g SM). Stir at room temperature to dissolve all solids. Charge 5.7 N HC1 in IPA (175 mL, 1.0 mol, 0.17 mol eq) via addition funnel over 10 minutes to form white solids. Stir the thin slurry at room temperature for 30 minutes. Charge 5.7 N HC1 in IPA (670 mL, 3.82 mol, 0.67 mol eq) followed by 5.6 N HC1 in IPA (110 mL, 0.62 mol, 0.11 mol eq) via addition funnel over 55 minutes. Stir the slurry for 35 minutes then assay the mother liquors for loss. Add 5.6 N HC1 in IPA (60 mL, 0.34 mol, 0.06 mol eq) over 10 minutes via addition funnel. Stir the slurry for 30 minutes then assay the mother liquors for loss. Filter to collect solids. Wash filtercake with isopropyl alcohol (2.8 L, 2 mL/g SM). Wash filtercake a second time with isopropyl alcohol (2.8 L, 2 mL/g SM). Dry filtercake to a constant weight by pulling air through the filtercake using vacuum. Obtain 1277 g of product as an off-white solid. HPLC: 99.9%.

[0084] The resulting compound exhibits a crystalline XRPD pattern (Figure 1), and is designated as Crystalline Form A. The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) is analyzed to verify the Si 111 peak position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short anti-scatter extension, and an anti-scatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. The diffraction pattern is collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. The experimental XRPD pattern is collected according to cGMP

specifications. The XRPD pattern collected is shown in Figure 1 (Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.01-40.00 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 1939 s, Scan Speed: 1.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission).

[0085] Characterization data for Crystalline Form A are summarized in Table 1 below:

Table 1.

a. Temperatures are rounded to the nearest °C; weight loss values are rounded to one decimal place.

Example 2 - Preparation of Crystalline Forms B and C

[0086] Crystalline Forms B and C are prepared as follows by using Crystalline Form A obtained from Example 1 above. The results are presented in Table 2 below:

Table 2.

a. Reported temperatures, times, and RH value are approximate.

b. About 25 mg scale. Concentration of IPA solution: 10 mg/mL.

c. About 27 mg scale. Concentration of IPA solution: 10 mg/mL. [0087] Crystalline Form B - Crystalline Form B is obtained from evaporation and slurry in water, slurry, slow and crash cooling in DCM, as well as slow cooling in 1-propanol. In addition, materials exhibiting XRPD patterns of Crystalline Form A with Crystalline Form B peaks result from evaporation in DCM, ethanol, HFIPA, and TFE. Material exhibiting XRPD pattern of Crystalline Form B with weak Crystalline Form A and Crystalline Form C peaks is observed from a crash cooling experiment in 1-propanol.

[0088] A high-resolution XRPD of Crystalline Form B is shown in Figure 4. The pattern appears to represent a mixture of Crystalline Forms B and A. Peaks at 18.5°, 20.7°, 25.7°, and 27.5° two-theta are likely from Crystalline Form A.

[0089] XRPD Data acquisition parameters for Figures 2B and 3 : INEL XRG-3000, X-ray

Tube: 1.54187100 A, Voltage: 40 (kV), Amperage: 30 (mA), Acquisition Time: 300 sec, Spinning capillary, Step size: approximately 0.03 °2Θ.

[0090] XRPD Data acquisition parameters for Figure 4: Panalytical X-Pert Pro MPD

PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 1939 s, Scan Speed: 1.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

[0091] Characterization data for Crystalline Form B are summarized in Table 3 below:

Table 3.

a. Temperatures are rounded to the nearest °C; weight loss values are rounded to one decimal place.

b. High-resolution XRPD.

[0092] Crystalline Form C - Crystalline Form C may be made by slow cooling in isopropanol. Material exhibiting XRPD pattern of Crystalline Form A with weak Crystalline Form C peaks results from a slow cooling experiment in ethanol; while the crash cooling experiments in ethanol and isopropanol afford XRPD pattern Crystalline Form C with weak Crystalline Form A peaks. [0093] Six scale-up attempts are conducted to prepare Crystalline Form C by cooling in isopropanol on approximately 50-150 mg scale (Table 4) and the solids tested by XRPD. At refrigerator temperature, precipitated solids yield Form B. Seeding with Form C after cooling in the refrigerator (no solids observed) and before placing in the freezer yield XRPD pattern of Form C with B peaks. Precipitation at freezer temperature results in solids with an XRPD pattern of Form C with A peaks. For a solution placed in the freezer after cooling to room temperature with a lower concentration (7 mg/mL compared to 10 mg/mL) yield Form B. By crash cooling (ambient solution placed into dry ice/isopropanol), solids generated are a mixture of Forms B and A. The last attempt on an approximate 50-mg scale generates a mixture of Forms A and C. The different outcome of these experiments suggest possible factors affecting the crystallization of Form C on a larger scale (e.g., concentration, temperature, cooling time, and seeding), and competitive crystallization of Forms A and B that are possibly more stable under the experimental conditions used. Note that Form C remains unchanged by XRPD after 22 days of ambient storage.

[0094] XRPD Data acquisition parameters for Figures 7A, C, and F: Panalytical X-Pert

Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 717 s, Scan Speed: 3.3 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

[0095] XRPD Data acquisition parameters for Figure 7B : Panalytical X-Pert Pro MPD

PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

[0096] XRPD Data acquisition parameters for Figure 7D: Panalytical X-Pert Pro MPD

PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 718 s, Scan Speed: 3.3 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

[0097] XRPD Data acquisition parameters for Figure 7E: Panalytical X-Pert Pro MPD

PW3040 Pro, X-ray Tube: Cu (1.54060 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.27min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission. Table 4.

a. Reported temperatures and times are approximate.

b. Concentration of IPA solution: 11 mg/mL.

c. Concentration of IPA solution: 10 mg/mL.

d. Seeded with Crystalline Form C (for XRPD of seeds see Figures 2C and 5) before moving into the freezer.

e. Concentration of IPA solution: 7 mg/mL.

[0098] A high-resolution XRPD of Crystalline Form C is shown in Figure 6. The pattern appears to represent a mixture of Crystalline Forms C and A. Peaks at 12.3°, 15.4°, 16.6°, 20.7°, and 25.7° two-theta are likely from Crystalline Form A.

[0099] XRPD Data acquisition parameters for Figures 2C, 5, and 7G: INEL XRG-3000,

X-ray Tube: 1.54187100 A, Voltage: 40 (kV), Amperage: 30 (mA), Acquisition Time: 300 sec,

Spinning capillary, Step size: approximately 0.03 °2Θ.

[00100] XRPD Data acquisition parameters for Figure 6: Panalytical X-Pert Pro MPD

PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range:

1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.2 min., Slit: DS:

1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

[00101] Characterization data for Form C are summarized in Table 5 below: Table 5.

a. Temperatures are rounded to the nearest °C; weight loss values are rounded to one decimal place; reported ΔΗ values are rounded to the nearest whole number.

b. High-resolution XRPD, reanalyzed after 22 days of ambient storage.

Example 3 - Preparation of Crystalline Form A

102] Commercially available reagents are used as received unless otherwise noted.

Reactions requiring an inert atmosphere are run under nitrogen unless otherwise noted.

Step 1 and 2:

103] 2-naphthylacetonitrile (4500 g) is dissolved in THF (32 L), 3.2 kg of (S)-(+)- epichlorohydrin is added and the solution cooled to -16 °C. A 2.0 M solution of sodium hexamethyldisilylazane in tetrahydrofuran (THF) (24.7 kg) is then added, keeping the internal temperature below -10 °C. This addition requires 2 hr 45 minutes to complete. The reaction mixture is then stirred an additional six hours at approximately -15 °C after which a sample is analyzed by HPLC. While keeping the internal temperature less than 0 °C, borane- dimethylsulfide (6.5 kg) is added over 36 minutes. After completion of the borane addition, the reaction mixture is slowly heated to 60 °C to reduce the nitrile to the amine. During this heat-up, an exotherm is noted which initiates at 45 °C. After heating at 60 °C for two hours a sample of the reaction mixture is analyzed by HPLC. The reaction mixture is cooled to 24 °C and transferred to a solution of 2M HCl over 1 hr. The two-phase mixture is heated to 50 °C and stirred for 1 hour at this temperature followed by cooling to 29 °C. The pH of the quenched reaction mixture is measured and found to be 5. Additional 2M HCl is added, the mixture heated to 50 °C and stirred for one hour, then cooled to 25 °C. The pH is measured and found to be 1. Reaction workup continues by the addition of isopropyl acetate (IP Ac), stirring, layer separation, and discard of the organic layer. Aqueous ammonia is added to the aqueous layer and the pH measured, which shows a pH of 8. Additional ammonia is added and the pH re-measured and found to be 8.5. Workup then continues by extraction with two extraction of the aqueous layer with IP Ac. The combined organic extracts are then washed with 5% dibasic sodium phosphate in water followed by a brine wash. The resulting organic layer is partially concentrated to azeotropically dry followed by dilution with IP Ac. p-Toluenesulfonic acid hydrate (4.9 kg) is then added in portions to precipitate the desired product as its pTsOH salt, which is isolated by filtration. The filtercake is washed with IP Ac and then dried to a constant weight to give 5785 g of the desired product as a white solid. Yield: 54%. HPLC: 98.2%.

Step 3 and 4:

Isolation

magnesium sulfate NA NA 0.5 g/g 2.9 Kg hydrogen chloride in isopropyl alcohol 5.7 M NA 1.0 mol eq. 0.90 L

1.5 mL/g

isopropyl alcohol 60.1 0.786 as required

SM

Ethyl alcohol 200 (special industrial 1.5 mL/g

80.25 0.786 as required denatured) SM

Step 3:

[00104] The amine-pTsOH salt (5785 g) obtained from step 2 is suspended in IP Ac (176

L) to give a slurry. Thionyl chloride (2.1 kg) is then added over one hour. Upon completion of the thionyl chloride addition the reaction mixture is stirred one additional hour and a sample is analysed by HPLC. Aqueous sodium hydroxide (5M, 6 mol equivalents) is added over one hour followed by four hours of additional stirring. The layers are allowed to settle and the pH of the aqueous layer is found to be 9. The layers are separated and the organic layer washed with 1M NaOH in water. The aqueous layers are combined and back extracted with IP Ac and the initial organic layer and the back extract combined. These combined organic layers are washed with 0.5M HC1 to extract (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane into the aqueous layer. The acidic aqueous layer is washed with a 1 : 1 mixture of IP Ac and THF to remove color. The aqueous layer is basified with aqueous ammonia followed by extraction with IP Ac. After layer separation the organic layer is washed with brine, dried over magnesium sulfate, and partially concentrated. After the concentration, hydrogen chloride in isopropyl alcohol (IP A) (1.0 mol equivalent of HC1, 0.90 L) is added to form the crude salt, which is isolated by filtration, washed with IP Ac and then partially dried. The wet cake is refluxed in IP Ac. The crude salt is refluxed in IPA and the solids isolated by filtration, washed with IP A, and then dried. > 99.5 HPLC area percent and 97.7 % chiral area percent purity. 1759 g of the desired product.

Step 4:

[00105] The crude (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

(1753 g) obtained from step 3 is dissolved in 20 volumes of hot ethanol (70 °C) and then filtered via an inline filter as a polish filtration. The dissolution vessel and the inline filter and transfer line are then rinsed with additional hot ethanol (61 °C) and the rinse combined with the filtrate. The combined filtrate and washes are partially concentrated in vacuo to approximately 11.5 total volumes (relative to crude (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride input) and then reheated to redissolve the solids. The solution is cooled to 65 °C and seed crystals added as slurry in ethanol. After stirring at approx. 65 °C to develop the seed bed, the slurry is cooled to room temperature. The resulting solids are isolated by filtration, the filtercake is washed with ethanol, and the washed solids dried. A total of 1064 g of tan product is obtained. >99.5 % for both chiral and achiral HPLC.

Step 5:

[00106] The (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (1064 g) obtained from step 4 is dissolved in 10.7 L of water while warming to 35 °C. Once all solids dissolve, the aqueous solution is washed with 1 : 1 THF:IPAc to remove most of the color. After the wash, aqueous ammonia is added to the aqueous layer and (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.OJhexane is extracted into IP Ac. The organic layer is dried over magnesium sulfate and then concentrated in vacuo to give an off-white solid. The solid is dissolved in IPA and transferred to a 22 L 3 -neck round bottom flask via inline filtration. Filtered hydrogen chloride in IPA is then added to reform the salt, which is isolated via filtration. The filtercake is washed with IPA and then dried to give 926 g of (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1. OJhexane hydrochloride as a slightly off-white solid.

[00107] An XRPD of the product is shown in Figure 8 and is consistent with Crystalline

Form A. The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short anti-scatter extension, and an anti-scatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. The diffraction pattern is collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD

PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 717 s, Scan Speed: 3.3 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

[00108] Figure 9 overlays the XRPD patterns from Figure 1 and Figure 8. There are some differences in relative peak intensities that are likely due to preferred orientation (PO). PO is the tendency for crystals, usually plates or needles, to pack against each other with some degree of order. PO can affect peak intensities, but not peak positions, in XRPD patterns.

[00109] An XRPD of the product after long-term storage is shown in Figure 10 and is consistent with Crystalline Form A. The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. The diffraction pattern is collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X- Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 719 s, Scan Speed:

3.3°/min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission. Observed peaks are shown in Figure 11. Observed, representative, and characteristic peaks for Crystalline Form A are listed in Tables 6a, 6b, and 6c, respectively, below.

Table 6a. Observed peaks for Crystalline Form A

°2Θ d space (A) Intensity (%)

6. E ) 7 + 0. 20 12 .85S 1 + 0.374 6

12. .26 ± 0 .20 7. 211 ± 0 .117 22

13. .78 ± 0 .20 6. 421 ± 0 .093 36

14. .49 ± 0 .20 6. 106 ± 0 .084 6

15. .42 ± 0 .20 5. 741 ± 0 .074 26

16. .55 ± 0 .20 5. 352 ± 0 .064 40

17. .15 ± 0 .20 5. 167 ± 0 .060 29

18. .19 ± 0 .20 4. 873 ± 0 .053 100

18. .50 ± 0 .20 4. 792 ± 0 .051 100

19. .45 ± 0 .20 4. 560 ± 0 .046 38

20. .06 ± 0 .20 4. 422 ± 0 .044 9

20. .46 ± 0 .20 4. 338 ± 0 .042 43

20. .68 ± 0 .20 4. 291 ± 0 .041 80

20. .96 ± 0 .20 4. 236 ± 0 .040 11

21. .54 ± 0 .20 4. 123 ± 0 .038 10

22. .90 ± 0 .20 3. 880 ± 0 .033 22

24. .69 ± 0 .20 3. 602 ± 0 .029 3

25. .17 ± 0 .20 3. 535 ± 0 .028 14

25. .44 ± 0 .20 3. 499 ± 0 .027 13

25. .69 ± 0 .20 3. 466 ± 0 .027 70

26. .36 ± 0 .20 3. 378 ± 0 .025 13

27. .52 ± 0 .20 3. 239 ± 0 .023 23

27. .76 ± 0 .20 3. 211 ± 0 .023 7

Table 6b. Representative peaks for Crystalline Form A

°2Θ d space (A) Intensity (%)

12.26 ± 0 , .20 7 , .211 ± 0. .117 22

13.78 ± 0 , .20 6 , .421 ± 0. .093 36

15.42 ± 0 , .20 5 , .741 ± 0. .074 26

16.55 ± 0 , .20 5 , .352 ± 0. .064 40

17.15 ± 0 , .20 5 , .167 ± 0. .060 29

18.19 ± 0 , .20 4 , .873 ± 0. .053 100

18.50 ± 0 , .20 4 , .792 ± 0. .051 100

19.45 ± 0 , .20 4 , .560 ± 0. .046 38

20.46 ± 0 , .20 4 , .338 ± 0. .042 43

20.68 ± 0 , .20 4 , .291 ± 0. .041 80

22.90 ± 0 , .20 3 , .880 ± 0. .033 22

25.69 ± 0 , .20 3 , .466 ± 0. .027 70

Table 6c. Characteristic peaks for Crystalline Form A

°2Θ d space (A) Intensity (%)

15.42 ± 0 , .20 5 .741 ± o . .074 26

16.55 ± 0 , .20 5 .352 ± 0. .064 40

17.15 ± 0 , .20 5 .167 ± 0. .060 29

18.50 ± 0 , .20 4 .792 ± 0. .051 100

19.45 ± 0 , .20 4 .560 ± 0. .046 38

20.46 ± 0 , .20 4 .338 ± 0. .042 43

20.68 ± 0 , .20 4 .291 ± 0. .041 80

22.90 ± 0 , .20 3 .880 ± 0. .033 22

25.69 ± 0 , .20 3 .466 ± 0. .027 70

Example 4

[0001] 558.9 mg of Crystalline Form A from Example 3 above is slurried in 5 mL dichloromethane. The preparation is stirred (300 RPM) in a sealed vial at ambient temperature for 16 days. White solids are isolated by vacuum filtration, rinsed with 1 mL of

dichloromethane, and briefly dried under nitrogen. Product is Crystalline Form A. An XRPD pattern of the product is in Figure 17. The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3-nm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and an antiscatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence.

Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A),

Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

Example 5 - Preparation of Crystalline Form B [0002] 470.9 mg of Crystalline Form A from Example 3 above is mixed with 5 mL of water in a 20 mL glass vial. The slurry is stirred at ambient temperature for 16 days with a stir bar to allow conversion to occur. The solids are collected by vacuum filtration and briefly dried under nitrogen.

Example 6 -Preparation of Crystalline Form B

[0003] 1 g of the product from Example 12 (Lot 1) below is stirred in 5 mL of Special

Industrial 200 (ethanol denatured) over weekend at ambient temperature. The mixture is filtered and rinsed with 2 mL of Special Industrial 200 (ethanol denatured) and followed by isopropyl acetate (2 x 3 mL). Pull dry the solids over 2 hours and then dry at 40 °C over 6 hours to give 0.81 g of product.

[0004] An XRPD shows the product is Crystalline Form B (Figure 12). The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRJVI 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short anti-scatter extension, and an anti-scatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. The diffraction pattern is collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.01-39.98 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission. Observed peaks are shown in Figure 13. Observed, representative, and characteristic peaks for Crystalline Form B are listed in Tables 7a, 7b, and 7c, respectively, below. Table 7a. Observed peaks for Crystalline Form B

°2Θ d space (A) Intensity (%)

6.04 ± 0.20 1 .620 ± 0. 84 13

12.12 ± 0.20 7.296 ± 0.120 6

13.21 ± 0.20 6.699 ± 0.101 21

14.86 ± 0.20 5.958 ± 0.080 8

15.13 ± 0.20 5.853 ± 0.077 5

16.02 ± 0.20 5.529 ± 0.069 1

16.90 ± 0.20 5.242 ± 0.062 4

17.41 ± 0.20 5.089 ± 0.058 14

18.23 ± 0.20 4.861 ± 0.053 10

18.94 ± 0.20 4.681 ± 0.049 79

19.19 ± 0.20 4.622 ± 0.048 100

19.91 ± 0.20 4.457 ± 0.044 4

21.05 ± 0.20 4.217 ± 0.040 11

21.27 ± 0.20 4.173 ± 0.039 2

21.74 ± 0.20 4.085 ± 0.037 4

22.55 ± 0.20 3.939 ± 0.034 6

23.59 ± 0.20 3.769 ± 0.032 16

23.79 ± 0.20 3.737 ± 0.031 43

24.39 ± 0.20 3.646 ± 0.029 23

25.34 ± 0.20 3.512 ± 0.027 1

26.06 ± 0.20 3.416 ± 0.026 2

26.61 ± 0.20 3.347 ± 0.025 1

27.15 ± 0.20 3.282 ± 0.024 2

28.15 ± 0.20 3.168 ± 0.022 24

28.66 ± 0.20 3.112 ± 0.021 13

29.47 ± 0.20 3.028 ± 0.020 13

Table 7b. Representative peaks Crystalline Form B

°2Θ d space (A) Intensity (%)

6.04 ± 0.20 14.620 ± 0.484 13

13.21 ± 0.20 6.699 ± 0.101 21

17.41 ± 0.20 5.089 ± 0.058 14

18.94 ± 0.20 4.681 ± 0.049 79

19.19 ± 0.20 4.622 ± 0.048 100

23.59 ± 0.20 3.769 ± 0.032 16

23.79 ± 0.20 3.737 ± 0.031 43

24.39 ± 0.20 3.646 ± 0.029 23

28.15 ± 0.20 3.168 ± 0.022 24

Table 7c. Characteristic peaks for Crystalline Form B

°2Θ d space (A) Intensity (%)

6.04 ± 0.20 14.620 ± 0.484 13

17.41 ± 0.20 5.089 ± 0.058 14

18.94 ± 0.20 4.681 ± 0.049 79

19.19 ± 0.20 4.622 ± 0.048 100

24.39 ± 0.20 3.646 ± 0.029 23

Example 7 - Crystalline Form C [0005] A turbid solution containing 458.2 mg of Crystalline Form A from Example 3 and 40 mL of IP A is generated at elevated temperature. The hot solution is filtered with a 0.2- μπι nylon filter into a clean vial and placed into a freezer. After two days, the solids are recovered by vacuum filtration and briefly dried under nitrogen. The solids are identified as a mixture of Crystalline Forms A and C. A slurry is generated with 42.2 mg of the mixture and 0.8 mL of a saturated DCM solution. (The saturated solution is generated with 65.4 mg of Crystalline Form A from Example 3 in 5 mL of DCM at ambient temperature. Excess solids are filtered from the solution the following day with a 0.2-μπι nylon filter.) The slurry is stirred, 100 RPM, with an agate ball at 2 °C for 3 weeks to allow conversion to occur. Solids isolated from the resulting suspension through vacuum filtration are stored at a temperatures between -25 and -10 °C.

[0006] An XRPD of the product is shown in Figure 14. The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short anti- scatter extension, and an anti-scatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. The diffraction pattern is collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission. Observed peaks are shown in Figure 15. Observed, representative, and characteristic peaks for Crystalline Form C are listed in Tables 8a, 8b, and 8c, respectively, below. Table 8a. Observed peaks for Crystalline Form C

°2Θ d space (A) Intensity (%)

6.97 + 0. 20 12 .677 ± 0.363 15

13.24 ± 0 .20 6. 683 ± 0 .101 13

13.68 ± 0 .20 6. 469 ± 0 .094 2

13.97 ± 0 .20 6. 333 ± 0 .090 3

14.39 ± 0 .20 6. 150 ± 0 .085 21

16.29 ± 0 .20 5. 435 ± 0 .066 6

17.74 ± 0 .20 4. 994 ± 0 .056 100

17.98 ± 0 .20 4. 929 ± 0 .054 27

18.03 ± 0 .20 4. 915 ± 0 .054 24

18.30 ± 0 .20 4. 843 ± 0 .052 13

19.85 ± 0 .20 4. 470 ± 0 .045 47

21.06 ± 0 .20 4. 214 ± 0 .040 6

21.32 ± 0 .20 4. 164 ± 0 .039 23

22.60 ± 0 .20 3. 931 ± 0 .034 95

23.35 ± 0 .20 3. 806 ± 0 .032 14

23.68 ± 0 .20 3. 754 ± 0 .031 25

23.94 ± 0 .20 3. 714 ± 0 .031 13

25.99 ± 0 .20 3. 426 ± 0 .026 14

26.52 ± 0 .20 3. 359 ± 0 .025 34

26.66 ± 0 .20 3. 340 ± 0 .025 16

26.90 ± 0 .20 3. 311 ± 0 .024 14

27.40 ± 0 .20 3. 252 ± 0 .023 6

27.99 ± 0 .20 3. 185 ± 0 .022 6

28.19 ± 0 .20 3. 163 ± 0 .022 3

29.06 ± 0 .20 3. 070 ± 0 .021 5

29.52 ± 0 .20 3. 024 ± 0 .020 7

Table 8b. Representative peaks for Crystalline Form C

°2Θ d space (A) Intensity (%)

6.97 ± 0.20 12.677 ± 0.363 15

13.24 ± 0 .20 6. 683 ± 0 .101 13

14.39 ± 0 .20 6. 150 ± 0 .085 21

17.74 ± 0 .20 4. 994 ± 0 .056 100

17.98 ± 0 .20 4. 929 ± 0 .054 27

18.03 ± 0 .20 4. 915 ± 0 .054 24

19.85 ± 0 .20 4. 470 ± 0 .045 47

21.32 ± 0 .20 4. 164 ± 0 .039 23

22.60 ± 0 .20 3. 931 ± 0 .034 95

23.68 ± 0 .20 3. 754 ± 0 .031 25

26.52 ± 0 .20 3. 359 ± 0 .025 34

Table 8c. Characteristic peaks for Crystalline Form C

°2Θ d space (A) Intensity (%)

17.74 ± 0.20 4.994 ± 0.056 100

Example 8 - Interconversion Slurry Experiments [0007] The proposed Energy - Temperature Diagram for Crystalline Forms A, B, and C is shown in Figure 16. In the diagram, the enthalpy (H) and free energy (G) isobars for each form are depicted as a function of temperature (7). Subscripts A, B, C, and L refer to

Crystalline Forms A, B, C, and liquid phase, respectively. Subscripts f, t, and m refer to fusion, transition point, and melting point, respectively. The graph assumes that the free energy isobars intersect at most once and, second, that the enthalpy isobars of the polymorphs do not intersect. The melting point of a polymorph is defined as the temperature at which the free energy isobar of the polymorph intersects the free energy isobar of the liquid. The transition temperature is defined as the temperature at which the free energy isobar of one polymorph intersects the free energy isobar of the second. Thus, at T_t both polymorphic forms have equal free energy, and consequently are in equilibrium with each other. Crystalline Form C is the stable solid phase below T_t,c→B (because the free energy of Crystalline Form C is lower than that of Crystalline Form B), Crystalline Form B is the stable solid phase between T_t,c→B and Tt,B→A, and Crystalline Form A is the stable solid phase above T_t,B→A - The low energy polymorph will have a lower fugacity, vapor pressure, thermodynamic activity, solubility, dissolution rate per unit surface area, and rate of reaction relative to the other polymorphs.

[0008] Interconversion experiments are performed to test the hypothetical

thermodynamic relationship between materials illustrated by the Energy - Temperature Diagram above. Interconversion or competitive slurry experiments are a solution-mediated process that provides a pathway for the less soluble (more stable) crystal to grow at the expense of the more soluble crystal form (Bernstein, J. Polymorphism in Molecular Crystals. Clarendon Press, Oxford, 2006; Brittain, H.G., Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999). Outside the formation of a solvate or degradation, the resulting more stable polymorph from an interconversion experiment is independent of the solvent used because the more thermodynamically stable polymorph has a lower energy and therefore lower solubility. The choice of solvent affects the kinetics of polymorph conversion and not the thermodynamic relationship between polymorphic forms (Gu, C.H., Young, V. Jr., Grant, D.J., J. Pharm. Sci. 2001, 90 (1 1), 1878-1890).

[0009] Binary interconversion slurry experiments between Crystalline Forms A, B, and

C in different solvent systems at temperatures spanning approximately 2 through 67 °C are summarized in Table 9 below. Saturated solutions are generated and then added to mixtures composed of approximately equivalent quantities of two of the polymorphs. The samples are slurried from overnight to three weeks and the solids harvested and analyzed by XRPD. The results of the interconversion studies indicate that the relative thermodynamic stability of the enantiotropes Crystalline Forms A, B, and C are correctly depicted by the proposed Energy - Temperature Diagram. In addition, T_t,c→_B is expected below 2 °C (is not determined), T_t,c_→A will be between 2 °C and ambient temperature, and T_IB→A will be between 37 and 54 °C.

Table 9. Binary Interconversion Slurries between Crystalline Forms A, B, and C

Duration and temperatures are approximate.

² Downward arrow indicates the peak intensities of the associated crystalline phase have decreased relative to those of the starting mixture. The length of time of the experiment is not sufficient to reach equilibrium; nevertheless, conclusions of the predominant form can be made based on the resulting mixture.

The solution-mediated interconversion process provides a pathway for the less soluble (more stable relative to the other) crystal to grow at the expense of the more soluble crystal form. However, when neither of the forms involved in the binary competitive slurry is the most thermodynamically stable form, the possibility of the most stable crystal to grow at the expense of the other two more soluble crystal forms can also result. This solvent-mediated polymorphic transformation is controlled by its nucleation rate, which is generally higher in a solvent giving higher solubility. In addition to the solubility, the strength of the solvent-solute interactions is also important. Degree of agitation and temperature also change the polymorphic transformation rate by influencing the crystallization kinetics of the more stable polymorph.

Example 9 - Accelerated Stress Conditions

[0010] Crystalline Forms A, B, and C are exposed to accelerated stress conditions for two weeks (Table 10 below). Based on XRPD, Crystalline Forms A and B remain unchanged at 30 °C/56% RH or 40 °C/75% RH within the time frame evaluated. However, Crystalline Form C converts to a mixture of Crystalline Forms A and B within two weeks at 40 °C/75% RH. Crystalline Form C is metastable at this condition. For Crystalline Form A, in the absence of seeds of the more stable polymorph, the critical free energy barrier for the nucleation of Crystalline Form B is not overcome in the solid state or in solvent mediated form conversion experiments within the time frame evaluated.

Table 10. Accelerated Stability Evaluation of Crystalline Form

[0011] T_t,B→A is between 37 and 54 °C. A mixture of Forms A and B (combination of portions 1 and 2 from Example 13), completely converts to Form A upon exposure to 230 °C (Table 11 below).

Experimental: Relative Humidity Stress [0012] The following relative humidity jars (saturated salt solutions are used to generate desired relative humidity) are utilized: 75% RH (NaCl) and 56 %RH (NaBr)

(Nyqvist, H., Int. J. Pharm. Tech. & Prod. Mfr. 1983, 4 (2), 47-48).

Table 11. Physical Stability of Mixture of Forms A and B

Time and temperature are approximate.

2 B = birefringent when observed by polarized light microscopy

Example 10 - Preparation of Crystalline Form B

[0013] A portion of Crystalline Form A from Example 3 above is slurried with water at ambient temperature for 16 days. Crystalline Form B is isolated. An XRPD of the product is in Figure 18. The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and an antiscatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 716 s, Scan Speed: 3.3 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

Example 11 - XRPD of Mixture of Crystalline Form A and Minor Quantity of Crystalline Form B [0014] An XRPD pattern of a mixture of Crystalline Form A and a minor quantity of

Crystalline Form B product is in Figure 19 (Example 13 for synthesis). The XRPD pattern is collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3^m-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and an antiscatter knife edge are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. Diffraction patterns are collected using a scanning position- sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b. Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 720 s, Scan Speed: 3.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

Example 12 - Preparation of Mixture of Crystalline Forms A and B

[0015] Commercially available reagents are used as received unless otherwise noted.

Reactions requiring inert atmospheres are run under nitrogen unless otherwise noted.

ammonia (aqueous) NA 0.889 2.0 mL/g SM 100 L

4 x 5 mL/g

methylene chloride 60 1.325 as required

SM

2-methyltetrahydrofuran 86.13 0.86 12.6 mL/g SM as required para-toluenesulfonic acid 54.2 Kg/284.9

190.22 NA 0.953 mol eq.

monohydrate mol

Steps 1 and 2

[0016] 2-naphthylacetonitrile (50 Kg) is dissolved in THF (250 L), 32 kg of (S)-(+)- epichlorohydrin is added and the solution cooled to -10 °C. A 2.0 M solution of sodium hexamethyldisilylazane in THF (299 L) is then added keeping the internal temperature below -10 °C. This addition requires 14 hrs., 14 minutes to complete. The reaction mixture is then stirred an additional four hours at approximately -10 °C, after which a sample of the reaction mixture is analyzed by HPLC. While keeping the internal temperature less than 0 °C, borane

dimethylsulfide (71 kg) is added over four hours and 33 minutes. After completion of the borane addition the reaction mixture is slowly heated to 60 °C to reduce the nitrile to the amine. During this heat-up, an exotherm is noted, which initiates at 45 °C. After heating at 60 °C for 14 hours and 46 minutes, a sample of the reaction mixture is analyzed by HPLC.

[0017] The reaction mixture is then cooled to 24 °C and transferred to a solution of 2M

HCl over 2 hours and 28 minutes and the reactor is rinsed with THF (22.3 Kg) and transferred to the HCl containing reaction mixture. The two phase mixture is heated to 45 °C to 55 °C and stirred for 1 hour 48 minutes at this temperature followed by cooling to 30 °C. The pH of the quenched reaction mixture is measured and found to be 1. Reaction workup continues by addition of IP Ac, stir, and separate the layers. Charge 1 M HCl solution to the organic layer, stir, separate the layers, and discard the organic layer. Aqueous ammonia is added to the combined aqueous layer and the pH measured which shows a pH of 9. Workup then continues by extraction with two extractions of the aqueous layer with IP Ac. The combined organic extracts are then washed with 5% sodium chloride solution. The resulting organic layer is partially concentrated to azeotropically dry and co-evaporation with methylene chloride four times and followed by dilution with methylene chloride and transfer of the reaction mixture via in-line filter to clean, dry reactor and diluting with IP Ac. p-Toluenesulfonic acid hydrate (54 Kg) is then added in portions to precipitate the desired product as its pTsOH salt and the reaction suspension is stirred over three hours at 10 °C to 15 °C and the product is isolated by filtration. The filter cake is washed with 2-methyltetrahydrofuran and followed by IP Ac then pull dried over two hours. The crude product is purified by stirring with 2-methyltetrahydrofuran over 11 hours 36 minutes at 10 °C to 15 °C and the product is isolated by filtration. The filtered solid is washed with 2-methyltetrahydrofuran and then dried to a constant weight to give 73.8 Kg of the desired product as a white solid. Yield = 73.8 Kg (62%). HPLC = 96.8%.

Steps 3 and 4

[0018] The amine-pTsOH salt (73.8 Kg) obtained from step 2 above is suspended in 2- methyltetrahydrofuran (738 L) to give a slurry. Thionyl chloride (26.4 kg) is then added over three hours. Upon completion of the thionyl chloride addition, the reaction mixture is stirred three additional hours. Aqueous sodium hydroxide (5M, 10 mol equivalents) is added over three hours followed by two hours of additional stirring. The layers are allowed to settle and the pH of the aqueous layer is checked and found to be 9. Water (2 mL/g, SM) is added, the reaction mixture is stirred 15 more minutes at room temperature, and the layers are separated and the organic layer washed twice with water. The aqueous layers are combined and back extracted with 2-methyltetrahydrofuran and the initial organic layer and the back extract combined. These combined organic layers are washed with brine, dried over magnesium sulfate, and partially concentrated. After concentration, hydrogen chloride in IPA (1.0 mol equivalent of HC1 in IP A) is added and stirred 2 hours to form the crude salt which is isolated by filtration, washed with 2- methyltetrahydrofuran and followed by IP Ac and then pull dried over 2 hours under vacuum. [0019] The crude product (82.6 Kg) obtained from above is dissolved in 14 volumes of hot ethanol (70 °C) and then filtered via an encapsulated carbon filter to improve the color. The dissolution vessel and the encapsulated carbon filter and transfer line are then rinsed with additional hot ethanol (70 °C) and the rinse combined with the filtrate. The combined filtrate and washes are partially concentrated in vacuo to approximately 5 total volumes (relative to crude product input) and then stirred over two hours at 0 °C. The resulting solids are isolated by filtration, the filter cake washed with cooled (0 °C to 5 °C) ethanol and followed by IP Ac and the washed solids then dried to give 33.6 Kg of the product as a slightly off-white solid. Yield = 33.6 Kg (73% yield). Achiral HPLC = 98%.

[0020] The material is then dried via cone drying. After drying, the material is sieved.

This is Lot 1.

[0021] A portion of the material (14 Kg) is then dissolved in 15 volumes of hot ethanol

(70 °C) and filtered via an encapsulated carbon filter to improve the color. The dissolution vessel and the encapsulated carbon filter and transfer line are then rinsed with additional hot ethanol (70 °C) and the rinse combined with the filtrate. The combined filtrate and washes are partially concentrated in vacuo to approximately 8 total volumes (relative to starting 14 Kg of (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride input) and then stirred over two hours at 18 °C. The resulting solids are isolated by filtration, the filter cake washed with cooled (5 °C to 10 °C) ethanol and followed by IP Ac and the washed solids then dried to give 9.4 Kg (67.1% of yield) of (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride as a white solid. This is Lot 2.

[0022] An XRPD of the product is shown in Figure 20. The XRPD is consistent with

Crystalline Form A with evidence of lower intensity peaks at 18.9°, 19.2°, 23.6°, 23.8°, 28.2°, and 28.7° 2Θ attributed to Crystalline Form B. The XRPD pattern is collected with a

PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) is analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample is sandwiched between 3- μιη-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, antiscatter knife edge, are used to minimize the background generated by air. Soller slits for the incident and diffracted beams are used to minimize broadening from axial divergence. Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b.

[0023] XRPD Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040

Pro, X-ray Tube: Cu (1.54059 A), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2Θ, Step Size: 0.017 °2Θ, Collection Time: 721 s, Scan Speed: 3.2 min., Slit: DS: 1/2°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

Example 13 - Preparation of Mixture of Crystalline Forms A and B

[0024] To a 2 L 3 neck round bottom flask with mechanical stirring, reflux condenser, nitrogen inlet, thermocouple, and heating mantle, is added 50 g of the product from Example 12 (Lot 1) above and EtOH Special Industrial (750 mL, 15 vol). The mixture is heated to reflux (77°C). Solids dissolve forming clear solution at 72°C. Loose charcoal slurry is added (5 g, 0.1 eq in 100 mL EtOH) and the mixture is stirred for 1 hour. Filter and rinse with hot EtOH (150 mL). Split filtrate into two equal portions.

Portion 1

[0025] Concentrate down to 10 vol (250 mL) at 50°C. Small amount of solids start to precipitate during concentration. Transfer to 500 mL 3 neck round bottom flask with mechanical stirring and allow to cool to room temp. Stir for 2 hours at room temp. Suspension forms. Filter and rinse with EtOH (50 mL, 2 vol) followed by IP Ac (50 mL). Pull dry on filter. Yield = 20.5 g (82%).

Portion 2

[0026] Concentrate down to 7 vol (175 mL) at 50°C. Small amount of solids start to precipitate during concentration. Transfer to 500 mL 3 neck round bottom flask with mechanical stirring and allow to cool to room temp. Stir for 2 hours at room temp. Suspension forms. Filter and rinse with EtOH (50 mL, 2 vol) followed by IP Ac (50 mL). Pull dry on filter. Yield = 19.8 g (79.2%).

[0027] Product from the two portions are combined and an XRPD pattern of the combined portions is in Figure 19 (Example 11).

Example 14 - Recrystallization Experiments with Trifluoroethanol [0028] A concentration of 200 mg/ml of QR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride from Example 12 and (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride from Example 13 in 500μ1 trifluoroethanol are heated to 50°C followed by cooling to 5°C. No solid material appears.

Example 15

[0029] Mixtures with a concentration of 75 mg/ml of (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride from Example 12 or 13 with 20 ml solvent, including water content, are prepared. Cooling times are varied. All experiments start at 25°C, followed by heating to 50°C at 5°C/min, followed by a waiting time of 30 minutes, followed by cooling to 10°C over different cooling times. The experiments with a cooling time of 2 and 24 hours have a waiting time of 30 minutes and the experiments with a cooling time of 13 hours have a waiting time of 7 hours at 10°C. Table 12 summarizes results. Starting material EE of 98% or greater shows good control of polymorphic behaviour and chemical purity.

[0030] Chemicals:

Ethanol special industrial 200: Ethanol 84.0-88.0%, isopropanol 7.5-10.5%, methanol 3.0- 5.5%), and methyl isobutyl ketone 0.8-1.1%)

Absolute ethanol: 99% purity or greater

Example 12: LC purity (area %) = 99.79. LC EE (area %) = 99.79.

Example 13 : HPLC purity (area %) = 96.29. HPLC EE (area %) = 96.29.

Table 12.

absolute

EtOH 13 13 2.5 7.99 100 industrial

EtOH 2 13 5 0 100 industrial

EtOH 13 13 2.5 3.62 100 industrial

EtOH 13 12 2.5 100 100 industrial

EtOH 24 12 5 100 99.81 industrial

EtOH 24 12 0 100 99.15 absolute

EtOH 2 12 5 100 99.80 absolute

EtOH 13 13 2.5 10.05 100 industrial

EtOH 24 13 0 8.16 100 absolute

EtOH 13 13 2.5 0 100 absolute

EtOH 13 13 2.5 0 100 absolute

EtOH 2 12 0 100 99.74 absolute

EtOH 2 13 0 0 100 industrial

EtOH 24 12 5 99.46 99.81 absolute

EtOH 2 12 5 100 100 industrial

EtOH 24 13 5 1.22 100 absolute

EtOH 24 13 5 0 100 industrial

EtOH 13 12 2.5 100 100 industrial

EtOH 13 13 2.5 2.51 100 absolute

EtOH 24 12 0 100 99.54 industrial

EtOH 13 12 2.5 100 100 absolute

EtOH 24 13 0 2.50 100 industrial

Claims

A method of crystallizing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms comprising mixing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material and pure ethanol, e.g., ethanol having a purity of 85% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 99% or greater, e.g., 99.5% or greater.

A method of crystallizing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms comprising crystallizing (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material having an enantiomeric excess (%EE) of (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride of 51% or greater, e.g., 60% or greater, e.g., 70% or greater, e.g., 80% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 96% or greater, e.g., 97% or greater, e.g., 98% or greater, e.g. 99% or greater.

The method of claim 2 comprising mixing the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material and pure ethanol, e.g., ethanol having a purity of 85% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 99% or greater, e.g., 99.5% or greater.

The method of any one of the preceding claims, wherein the (lR,5S)-l-(naphthalen-2-yl)- 3-azabicyclo[3.1.0]hexane hydrochloride starting material has an enantiomeric excess (%EE) of (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride of 51% or greater, e.g., 60% or greater, e.g., 70% or greater, e.g., 80% or greater, e.g., 90% or greater, e.g., 95% or greater, e.g., 96% or greater, e.g., 97% or greater, e.g., 98% or greater, e.g. 99% or greater.

The method of any one of the preceding claims comprising dissolving the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol.

The method of any one of the preceding claims comprising dissolving the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in 1-20 ml of the ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 5-20 ml of the ethanol per gram of the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 10-20 ml of the ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 14 ml of the ethanol per gram of the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material.

7. The method of any one of the preceding claims, wherein the concentration of the

(lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol is 10-150 mg/ml, e.g., 20-150 mg/ml, e.g., 50-100 mg/ml, e.g., 50 mg/ml, e.g., 75 mg/ml.

8. The method of any one of the preceding claims comprising dissolving the (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol under heat, e.g., heating a mixture of the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material in the ethanol to 30 °C or higher (e.g., 30 °C-100 °C), e.g., 40 °C or higher (e.g., 40 °C-100 °C), e.g., 50 °C or higher (e.g., 50 °C-100 °C), e.g., 60 °C or higher (e.g., 60 °C-100 °C), e.g., 70 °C or higher (e.g., 70 °C-100 °C, e.g., 70 °C), e.g., 80 °C or higher (e.g., 80 °C-100 °C), e.g., 90 °C or higher (e.g., 90 °C-100 °C), e.g., 100 °C or higher.

9. The method of any one of the preceding claims comprising improving the color of the mixture by removing colored impurities, for example, by filtering through an

encapsulated carbon filter and/or adding charcoal (e.g., loose charcoal slurry in ethanol) and filtering to remove the charcoal.

10. The method of any one of the preceding claims further comprising concentrating the ethanol.

11. The method of any one of the preceding claims further comprising concentrating the ethanol under vacuum.

12. The method of any one of the preceding claims further comprising concentrating the ethanol under heat, e.g., at 80 °C or less (e.g. above room temperature to 80 °C), e.g., 70 °C or less (e.g., above room temperature to 70 °C), e.g., 60 °C or less (e.g., above room temperature to 60 °C), e.g., 50 °C or less (e.g., above room temperature to 50 °C, e.g., 50 °C), e.g., 40 °C or less (e.g., above room temperature to 40 °C), e.g., 30 °C or less (e.g., above room temperature to 30 °C).

13. The method of any one of the preceding claims further comprising concentrating the ethanol to 1-10 ml ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride starting material, e.g., 8 ml ethanol per gram of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material.

14. The method of any one of the preceding claims further comprising cooling the ethanol, e.g., to 30 °C or less (e.g., 0 °C-30 °C), e.g., room temperature or less (e.g., 0°C to room temperature), e.g., 20 °C or less (e.g., 0 °C-20 °C), e.g., 10 °C or less (e.g., 0°C-10 °C), e.g., 5 °C or less (e.g., 0 °C-5 °C), e.g., 18 °C, e.g., 5 °C.

15. The method of claim 14 further comprising stirring the ethanol during and/or after

cooling.

16. The method of any one of the preceding claims further comprising seeding with (1R,5S)- l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A, e.g., seeding the mixture of the (lR,5S)-l-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride starting material and the ethanol with (lR,5S)-l-(naphthalen-2-yl)-3- azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A.

17. The method of any one of the preceding claims further comprising isolating (1R,5S)-1- (naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride Crystalline Form A substantially free of other crystalline forms, e.g., isolating by filtration, e.g., isolating by filtration and, optionally, rinsing with a solvent, e.g., ethanol (e.g., the pure ethanol) and/or isopropyl acetate.